Sensory experience during early life can have profound and long-lasting effects on brain function. During critical periods in brain development, patterns of neural connectivity are especially susceptible to the shaping influence of experience. The proposed research will investigate, at the cellular and molecular levels, how experience modifies the brain and what mechanisms underlie critical periods. The results could have a major impact on our ability to treat a wide variety of human dysfunctions, particularly those resulting from birth defects, childhood disease or injury which necessarily entail abnormal environmental influences on brain development. The experimental system is a portion of the central auditory pathway in barn owls that is involved with sound localization; the barn owl's hearing, sound localization capabilities and associated neural pathways are similar to those of humans. Behavioral studies have shown that sound localization is shaped powerfully by an interaction of auditory and visual experience during early life, and the sensitive and critical periods have been characterized in detail. A neural correlate of the behavioral plasticity has been found in the optic tectum (superior colliculus), where neurons respond to both auditory and visual stimuli in a space-specific manner. Large adaptive changes in the auditory spatial tuning of these neurons are induced during early life either by chronic monaural occlusion (which changes the values of sound localization cues) or prismatic displacement of the visual field (which changes the locations to which cue values correspond). Neurophysiological, pharmacological and anatomical techniques will be used to study the mechanisms that underlie these experience-dependent changes. Digitally synthesized sound delivered through earphones will be used to describe the changes in auditory spatial tuning in terms of changes in unit tuning for localization cues. The sites in the auditory pathway where the adaptive changes take place will be identified physiologically using acute and chronic unit recording. A variety of histological techniques will be used to search for anatomical correlates of the plasticity. Once the site of plasticity is determined, the dynamics of the adjustment process, the nature of the instructive signal, and the pharmacological basis of the process will be investigated. With this information in hand, cellular and molecular correlates of the sensitive and critical periods that regulate these adaptive changes will be determined, and attempts will be made to block or restore the plasticity. The results of this research will reveal general principles of brain development, the consequences of early normal and abnormal experience, and the strategies used by the brain to deal adaptively with different kinds of sensory challenges.